Abstract Autophagy is an essential, fundamentally important catabolic pathway in which double membrane-bound vesicles form in the cytosol and encircle macromolecules and organelles to permit their degradation after fusion with lysosomes. As post-mitotic, non-dividing cells, neurons are highly susceptible to the accumulation of damaged proteins and organelles. Their complex, polarized cellular architecture, and their inability to dilute insults by cell division renders them particularly sensitive to accumulation of toxic protein aggregates and defective organelles. Neuronal survival thus depends heavily on maintaining protein quality control by efficient degradation mechanisms. Autophagy is highly active in neurons and functions to eliminate misfolded proteins, which are hallmarks of many neurodegenerative diseases. Alzheimer?s disease (AD) is a neurodegenerative disorder that is especially prevalent among elderly populations and is characterized by progressive neuron loss and cognitive decline, occurring in the context of protein aggregation and deposition. Amyloid plaques and neurofibrillary tangles of tau are the two defining histopathological hallmarks of AD pathology, and among the known risk factors for AD, aging is the most prominent. In neurodegenerative disease, autophagic vesicles often accumulate, indicative of a pronounced impairment in neuronal autophagy. In AD, immuno-electron microscopy analysis of AD patient brains reveals striking accumulations of autophagic vacuoles in the cell bodies and axons of cortical neurons. In the parent project upon which this supplement proposal is based, we have been studying the molecular genetic regulation of autophagy for neurotherapeutics application, and we have defined MAP4K3 as a central regulator of nutrient sensing, whose inhibition results in robust activation of productive autophagy in neurons. Here we propose to test if an antisense oligonucleotide (ASO) directed against MAP4K3 can ameliorate disease phenotypes in a recently developed, highly representative AD mouse model, the P301S tau x ApoE4 knock-in model, and in neurons derived from late-onset (sporadic) Alzheimer?s disease (LOAD) patients. Through the pursuit of these aims, we will determine if autophagy modulation by MAP4K3 inhibition could represent a novel therapy for AD and related dementias, and if successful, our work will set the stage for further development of MAP4K3 human ASOs as a viable treatment for AD and related dementias. As an ASO drug is already a disease-modifying therapy approved for use in human patients in a neurodegenerative disease, our strategy has excellent potential to advance to the clinic, if successful.